SI9200404A - Pharmaceutical composition and process for the preparation thereof - Google Patents

Abstract

The invention relates to two phase pharmaceutical compositions comprising as active ingredient an MAO inhibitor and an uptake inhibitor together with usual pharmaceutical auxiliaries. The compositions can be used for the treatment of neurodegenerative diseases. As active ingredient optionally N-(1-phenyl-isopropyl)-N-methyl-propinylamine or N-(4-fluoro-phenyl)-isoprop-1-yl-N-methyl-propinylamine or their salts, optically active isomers or metabolites are used both as MAO inhibitor and as uptake inhibitor.

Description

CHINOIN GYOGYSZER- ES VEGYESZETITERMEKEK GYARA RT.

Pharmaceutical preparation and process for its preparation

The invention relates to a pharmaceutical composition suitable for the treatment of neurodegenerative diseases containing ingredients which result in time and mass-appropriate concentrations in both the blood and the brain, and the method for its preparation.

Monoamine oxidase (MAO) is known to be one of the major metabolite enzymes (Blaschko H. Pharmacol. Rev. 4, 415, (1951)) of biogenic amines present in human nerve cells. Due to its activity, biogenic amines, which play an essential role in neurotransmission, are degraded into inefficient metabolites. In some diseases, the level of biogenic amines in the brain is known to decrease.

Agents that inhibit the metabolite enzyme (metabolite enzymes) can restore the normal level of these amines. For this reason, MAO inhibitors have been introduced into human therapy. It has been observed that MAO inhibitions can lead to a series of side effects associated with an increase in tyramine (which is a structurally biogenic amine) (a cheese reaction) that originates from foods and can lead to an increase in blood pressure and which can be fatal. (Piackar et al., Psychopharmacology 73.3087, (1981)).

MAO exists in two forms called MAO-A and MAO-B. By selectively inhibiting Form B, Form A is capable of breaking down tyramine, which is a mixed-type substrate, and dangerous side effects can be prevented. This can be observed in the case of (-) deprenyl, [(-) N - (- 1-phenyl-isopropyl) -N-methyl-propynylamine hydrochloride)], which selectively and irreversibly inhibits the MAO-B enzyme (Elsworth et al., Psychopharmacology

57.33, (1978))].

Due to irreversible inhibition, the restoration of enzyme activity may be the result of new re-synthesis of the enzyme.

The development of irreversible enzyme inhibition involves two stages. The first is reversible and only the formation of the second enzyme-inhibitor complex becomes irreversible. The half-life of enzyme regeneration is 7-8 days. (Oreland et al., J. Neural. Transm. Suppl. 32,55-59, (1990)).

An overview of substrate specificity for enzymes and selectivities of the best known inhibitors was published by Dostert and colleagues. (Medicinal Research Reviews, Vol. 9, No. 1. 45-89, (1989)).

Ballard (Science 219, 979-980, (1980) and Burns (Proc. Nati. Acad. Sci. 80, 4546-4550, (1983)) have been described to challenge MPTP (l-methyl-4-phenyl-l. 2,3,6-tetrahydropyridine) due to its neurotoxic effect on human Parkinson's syndrome and similar symptoms may be observed in animal experiments MPTP causes selective damage to corpus striatum dopaminergic neurons. Parkinson's disease It is known that this effect of MPTP can be prevented by MAO inhibitors, especially depressant. The preventative role of (-) - depressant is due to the inhibition of MPTP ⁺ conversion to MPP ⁺ (Nature, 311, 467, (1984)). MPTP-induced neurons can also be retained by dopamine uptake inhibitors (Proc. Nati. Acad. Sci. USA, 82, 2175, 1985) as mazindole, thereby inhibiting the active uptake of MPP ⁺ (methyl-phenyl-pyridinium ion) into dopaminergic neurons.

During the operation of MAO, free radicals of hydrogen peroxide and oxygen are formed, which can lead to oxidative damage to neurons. MAO can also form ammonia and some heterocyclic isoquinolines, which can be considered neurotoxic. (Maret et al., Drug metabolism. Reviews, 22, 291-332, (1990); P. Riederer et al., Acta Neurol. Scand. 126, 41, (1989); Benedetti and Dostert, Biochem. Pharm. Vol. 38, 555 (1989).

It is known to cause the neurotoxic agent DSP-4 (N- (2-chloroethyl) -N-ethyl-2bromo-benzylamine), releasing noradrenaline (NA) selectively from central and peripheral noradrenergic neurons (Grzanna et al., J. Histochem Cytochem., 1435-1442, 1989).

It is further known that

- that reuptake inhibitors, such as desipramine (10,11-dihydro-N-methyl-5-Hdibenz (6,7) azepine-5-propanamine), inhibit the effect of DSP-4 on NA release (Jonsson et al., Neuroscience, 7, 2895, (1982); Ross No. J. Pharmacol., 58, 521, (1976)), and that

- MDL 72974A ((E) -4-fluoro-beta-fluoro-ethylene benzene butanamine), a highly selective MAO-B inhibitor, does not have the ability to block catecholaminergic re-uptake and cannot prevent DSP-4-induced toxicity (Finnegen et al. Eur J. of Pharmacol. 184, 119-126, (1990).

It has been shown that (-) - deprenyl cannot be considered as simply an easily selective, irreversible MAO-B inhibitor. It has been found to inhibit the uptake of dopamine, noradrenaline and tyramine in the nerve endings and into the peripheral ganglions, but only at extremely high doses (Knoll, Advances, and Biochem. Psychopharmacology Vol. 5, 393,1972). It should be remembered that, in addition to its inhibitory effect on MAO, it has an inhibitory effect on uptake.

Our goal was to prepare a pharmaceutical preparation with optimal properties for the treatment of neurodegenerative diseases.

During our experiments, we found the following:

1.) Long-term MAO inhibition can only be achieved if the inhibitor concentration in the brain and blood reaches a sufficiently high concentration (15-40 pmol / mg tissue). If the inhibitor concentration is too high (30 mg / day), the metabolite concentration will also be high enough to cause an undesirable psychostimulant effect and / or loss of inhibitor selectivity (MAO-A will also be inhibited).

2.) Deprenyl and p-fluoro-deprenyl (N- (4-fluoro-phenyl) -isoprop-1-yl) -N-methylpropynyl-amine) show their activity both as the original (unchanged) compound and as metabolites.

The results are explained in Figures 1 and 2.

Following oral administration of alternately and positionally radiolabeled deprenyl and p-fluoro-deprenyl ( ³ H ring and propargyl ¹⁴ C (1.5 and 10 mg / kg), respectively, the distribution of compounds in the 15 brain regions (brain sections in The pairs were studied separately in 25 brain regions and in plasma for 96 hours as a function of time, and it was found that the unchanged compound was rapidly (15 min) absorbed and penetrated into the central nervous system. and metabolites can be found in tissues for a long time.

The simultaneous presence and equal abundance of both mariques indicate an unaltered molecule (data refer to molar concentrations calculated on the basis of both mariums). Due to the rapid change observed in the ³ H / ¹⁴ C injected tissue ratio, our experiments indicate significant metabolite formation (amphetamine, methylamphetamine, p-fluoro-methylamphetamine and p-fluoro-amphetamine) and their presence in the brain.

3.) Potential metabolites of deprenyl and p-fluoro-deprenyl (methylamphetamine, amphetamine and p-fluoro-methylamphenamine, or p-fluoro-amphetamine) have significant uptake inhibition efficiency. In vivo, MPTP neurotoxicity can be prevented without significant MAO inhibition. The results are shown in Tables 1, 2 and 3. The experiments were performed using the Heikilli method (Nature, 311.467-469, (1984)).

4.) Potential metabolites of deprenyl and p-fluoro-deprenyl (methylamphetamine, amphetamine and p-fluoro-methylamphetamine, or p-fluoro-amphetamine) are able to prevent in vivo at a dose of 1-5 mg / kg (ip) with DSP-4 generated neurotoxicity without developing MAO inhibition.

The results are shown in Table 8.

The experiments were performed by Finnegan method (Finnegan et al., Eur. J. Pharmacol., 184; 119-126, (1990)).

The metabolites used in high concentration (10 mg / kg; i.p.) in vivo enhanced the toxic effect of DSP-4, as indicated by animal death.

5.) To prevent neurotoxicity, either a short-term properly high concentration of the unchanged compound (the concentration required for complete irreversible MAO-B inhibition) is required, or - due to reversibility of inhibition of uptake - the long-term presence of metabolites.

We have found that maximum impact can be achieved if both conditions are met.

The invention relates to biphasic pharmaceutical compositions comprising as active ingredient a compound with an inhibitory effect on MAO and a compound with an inhibitory effect on uptake together with conventional excipients.

The compounds of the invention contain, as active ingredient, 5-95% by weight of a reversible or irreversible MAO inhibitor, 5-95% by weight of the uptake inhibitor, with a prolonged action in a ratio of 1-19: 1-19, with a ratio of 1 : 1,1: 2 or 1: 3.

Depending on the patient's condition, the severity of the clinical picture, and the individual patient's sensitivity, the preparation is administered at a dose of 5-20, preferably 10 mg / day.

To the extent that the uptake inhibitor does not have a prolonged action, we use the retarder-derived inhibitor.

Deporonyl, p-fluoro-deprenyl, their salts and the like can be used as MAO inhibitors. optically active isomers.

Deprenyl, p-fluoro-deprenyl or a compound of the general formula I can be used as inhibitors of uptake

in which R ^{1 is a} straight or branched alkyl group, C? 10 phenylalkyl group, or a phenyl group, or C3 ^ cycloalkyl group, R ² is a straight or branched alkyl group or an alkyl group substituted with a hydrogen atom, a hydroxy-CM alkoxy group, or with one or two phenyl groups, a phenyl group or a C ₃ ^ cycloalkyl group, provided that R ¹ and R ² contain at least 3 carbon atoms, or acid addition salts or metabolites thereof.

As the compound of general formula I, N-propyl-1-phenyl-2-pentylamine or its acid addition salt, N-propyl-1-phenyl-2-butylamine or its acid addition salt, or N-propyl-1-phenyl- 2-hexylamine or its acid addition salt.

The biphasic compositions according to the invention can be prepared by methods known per se in the form of pellets, tablets, coated tablets, transdermal preparations, dragees, microcapsules containing suspension, capsules, coated capsules, oral suspensions and injection suspensions, using known excipients substances.

The following materials can be used as auxiliaries:

a. ) As fillers: sucrose, lactose, mannitol, starch, starch-talc-sucrose, calcium phosphate, aqueous-alcoholic solution of polyvidone (polyvinylpyrrolidone), etc.

b. ) Retard Auxiliaries:

lipophilic base (stearic acid, stearic acid palmitate, glycerylditripalmitate stearate, etc.);

other excipients known in pharmaceutical technology: Eudragit derivatives, etc .;

cellulose derivatives: HPMC, CMC, EC and their salts.

c. ) Granulation fluid: water, ethanol, ethanol-water, isopropanol, isopropanol.

d. ) Binders: PVP / VA, Eudragit derivatives, cellulose derivatives and their salts.

We can also work by preparing the pharmaceutical preparation in situ, i.e., administering to the patient at the same time a dose of MAO inhibitor necessary to achieve a continuous 98% MAO inhibition and receiving a dosage inhibitor necessary to achieve continuous inhibition of administration .

The preparation of deprenyl, p-fluoro-deprenyl and compounds of general formula I is described in U.S. Pat. 4,564,706; in European patent no. 186,680 and Portuguese Pat. 85.799.

EXAMPLES

1. The two-phase tablet is prepared by a method known per se:

Inner phase: prepared with double granulation

a. )

Deprenyl: 5 mg

Methocel k 4 M premium: 50 mg

Lactose: 20 mg

Quantum satis isopropanol for granule preparation

b. )

Deprenil: 10 mg

Amylum maydis: 40 mg

Avicel PH-101: 20 mg

PVPK-25: 10 mg

Quantum satis isopropanol for granule preparation (distilled water may also be used)

External phase:

Mg stearate: 8 mg

Talc: 15 mg

Aerosil-200: 2 mg

2. Preparation of retard tablets containing 15 mg deprenil

Ingridients Deprenil 15 mg Stearic acid 30 mg Eudragit RSPM 45 mg Collidon VA 64 47 mg Carbopol 940 35 mg Sterotex 25 mg Magnesium stearate 3 mg 220 mg

(tablet diameter 8 mm)

Tablet technology

1. Preparation of granules by a known dry granulation method.

Powder mixing sequence:

Collidon VA 64, Carbopol 940, stearic acid, Sterotex (atomized) (hydrogenated cottonseed oil), Eudragit® RSPM (acrylic and methacrylic acid ester copolymer), deprenyl.

2. Tableting the powder mixture with an eccentric tablet at low speeds per minute.

Results of the dissolution test

Three parallel measurements were performed

Each cell contained 15 tablets.

a. ) 316.5 cg / 15 pieces

b. ) 316.0 cg / 15 pieces

c. ) 319.0 cg / 15 pieces

The medium used to dissolve was artificial pepsin-free gastric juice. (Ph. Hg. VII).

Dilution is zero. d = 1 cm X = 256 cm

Results

Time (minutes) Dissolved active ingredient (%)

10 4.5 15 9.0 30 21.0 60 31.2 90 47,7 120 39.3 150 41,1 180 48,6 240 51.9 300 63,3 360 69,0 420 (7 hours) 75,6

3.) Preparation of two-phase pellets

- Prepare fast and slow pellets with body components:

* FAST PELLETS

- Neutral pellets (sugar beads) 61.1 mg - Deprenil 16.3 mg - Lactose 16.6 mg - Polyvidone (K30) 6.3 mg * HONORARY PELLETS - Neutral pellets (sugar beads) 44,6 mg - Deprenil 11,9 mg - Lactose 11,9 mg - Polyvidone (K30) 4.6 mg - Ethylcellulose around 8,4 mg - Talc around 16.9 mg - Castor oil around In mg

- Manufacturing process

Sucrose crystals were coated with a starch / talc / sucrose mixture and an aqueous alcoholic solution of Polyvidone and sucrose (sugar bead).

Apply a mixture of deprenyl hydrochloride and lactose to the microgranules using an alcoholic solution of Polyvidon.

In the case of the slow pellet, an alcohol lacquer of ethylcellulose (plasticized with castor oil) and talc is applied to the microgranules obtained.

To obtain the required fast and slow pellets, the capsule is mixed in a manner known per se by the desired method of the desired multiplicity of fast and slow pellets.

4. Preparation of a two-phase transdermal preparation (UG-191)

Ingridients: Carbowax® 35000 1.0 Carbowax® 4000 16.0 Carbowax® 400 53,0 1,2-Propylene glycol 2.0 Xanthan gum 15.0 Deprenil 7.0 Cremophor® EL 6.0

100,0

Technology:

The ingredients of Carbowax were melted and the mixture was poured into an Erweka type mixing vessel at 50 ° C and stirred at Step 6. The deprenil was dissolved and suspended in a mixture of propylene glycol and Cremophor EL at 50 ° C, and the mixture was added to the mixer in portions (50 g each). container. After each meal, the mixture was stirred for 1 minute. Finally, at an increased rate (grade 9), xanthan gum was added in portions (5 g each). After each meal, the mixture was stirred for 1 minute. The stirring rate was then reduced to 3.5 and stirring continued until cooling (about 1.5 hours). The active substance content is 6.84% and the stability is adequate.

Liquid crystalline state: 100%, with translucent solid crystals of 8-10 / im. [Cremophor® EL: glycerin-polyethylene glycol-ricinoleate.

Xanthan gum: polysaccharide].

Pharmacological information:

When designing experimental conditions, the following information must be taken into account.

Direct in vivo measurement of the inhibitory efficacy of metabolites on uptake was not possible due to their reversible nature.

The efficacy of the MAO-B inhibitor can be measured peripherally in pigs using blood MAO-B activity as an indicator (blood cells derived from other species do not contain well-measurable MAO-B enzyme activity).

By measuring the temporal dependence of DSP-4 neurotoxicity in rats (using the hippocampus norepinephrine content as an indicator) after prior treatment with various dosage forms, it was demonstrated that there was a correlation between the lack of DSP-4 neurotoxicity and adequate but not extremely high levels of deprenyl metabolites in the blood.

In a series of experiments, the constant level of deprenyl metabolites in the blood of domestic pigs was measured by analytical techniques, and the activity of MAO in the platelets, brain, and liver was determined.

The experiments were performed on female domestic pigs (large white) weighing 20 to 25 kg. The pigs were kept in separate cages during the experiments and fed to them as they had been given before.

Animals were treated orally with 5, 7.5, 10, 15 mg (-) - deprenyl in the pellet and with 10 mg i.v. Blood samples (5 ml) were collected at 0, 0.08, 0.25, 0.5, 0.75,1,1,5, 2, 3, 4, 6, 12, 24 and 48 h in centrifugation tubes containing 500 IU of heparin for analytical measurement. Samples were centrifuged at 1500 rpm for 10 min to separate the plasma. Metabolites were determined by gas chromatographic method using Hp-5890 gas chromatograph and elution time for methylamphetamine 21.4 min.

The results are shown in Figure 3.

DSP-4 neurotoxicity inhibition was measured in rats. A Finnegan program was used for the treatment of rats (Finnegan et al. Eur. J. Pharmacol. 184; 119126; [1990]).

We used Wistar male rats weighing 170-200 g. Animals were caged with six animals each at constant temperature (22 ° C) in a room that was illuminated for 12 h daily. Feed and water were freely available. Rats were pretreated orally with 3 mg / kg of the combination of Example 3 (1 mg / kg fast (F) + 2 mg / kg slow (S)), 1, 2, 4 and 8 hours before DSP-4 treatment (50 mg / kg; intraperitoneal).

The animals were fasted for 24 h before pretreatment with (-) depressant. The hippocampus of rats was excised and noradrenaline content was measured by HPLC.

The results are shown in Figure 4.

As can be seen from Figure 4, 3 mg / kg deprenyl can p.o. prevent neurotoxicity 50 mg / kg DSP-4 i.p. in rats. In the case of a control (rapid) preparation, this prevention is high in the first period (86.1%), but it declines exponentially and reaches the level of control treated with DSP-4 (19.6%) after 8 hours. The formulation for which patent protection is claimed results in 58.8% inhibition, the inhibition being substantially equal (54.5%) to the inhibition of the control preparation (51.5%) after 2 hours but significantly higher (43. 31%) as in controls (16%) and practically does not change during 8 hours. In the case of treatment with 4 mg / kg depressant, it was found that the control (fast) preparation facilitated the neurotoxicity of DSP-4 as a function of time as opposed to the preparation (fast and slow) for which patent protection was required. (See Figure 5). This means that the dosage of the fast ingredient cannot be increased indefinitely without any undesirable side effects.

In contrast, the use of preparations for which protection is required will increase MAO-A inhibition by increasing the amount of slow work, which means that there will be a loss of selectivity for deprenyl.

The results are given in Table 4.

Table 4

Percent inhibition of MAO with deprenyl preparations

Preparation The brain MAO-B MAO-A 1 mg / kg (tablets) 88.02 ± l, 49 2.55 ± 0.56 0.5 + 0.25 mg / kg 85.84 ± 4.16 14.83 ± 3.37 (fast and slow) 0.5 + 1.0 mg / kg 90.50 ± 3.10 27.28 ± 3.93 (fast and slow)

In the case of transdermal preparations, the control group was treated orally with 10 mg (-) - deprenyl in a gelatin capsule.

Blood samples were taken to determine MAO-B activity at 0, 3, 6, 24, 48, 72, and 96 h. At 96 h, after blood samples were taken, pigs were killed and MAO-B and MAO-A activity determined in their excised brain.

The second group was treated as a control with a transdermal preparation UG-111 containing 10 mg (-) - deprenyl. Blood samples were taken at 0.3,6,24 and 48 h. Transdermal preparations were removed at 24 h. The patch and its nylon shielding were used to determine the content of the remaining (-) depressant in the preparations. The skin was washed with cotton wool with ethanol, which was also used for HPLC determination. Pigs were killed at 48 h and MAO-A and MAO-B activity determined in the brain.

The third group of pigs was treated as a control with UG-167 containing 20 mg (-) - deprenyl. Blood samples were taken at 0, 3, 6, 24, 48 and 72 h. The patches were removed at 48 h and the entire procedure described in group 2 was performed.

Four groups of pigs were treated with UG-191 containing 30 mg (-) - deprenyl. Blood samples were taken at 0, 3, 6, 24, 48, 72, and 96 h. The patches were removed at 48 h and the complete procedure described for group 2 was performed.

We took blood from v. cava cranialis with a 20 ml plastic injection syringe containing 1.5 ml 7.6% sodium citrate solution. The volume of blood collected was 18.5 ml each.

MAO activity was measured radiometrically according to Wurtman and Axelrod methods (Biochem. Pharmacol. 12.1414-19; 1963) with slight modification (K. Magyar in: Monoamine Oxidases and their Selective Inhibition. Ed .: K. Magyar, Pergamon Press, Ak ^ demiai Kiado, Budapest 11-21; 1980).

Blood platelets were prepared using the method described by Willberg and Oreland (Med. Biol. 54: 137-44; 1976).

Table 5

Absorption of (-) - depressants from transdermal preparations as a function of time in pigs. (The residual (-) - depressant content of the patches was determined by HPLC technique.

Transdermal preparation Duration experiment (h) The rest deprenil% + S.D. UG-111 (control) 10 mg 24 14.2 ± 5.5 UG-167 (control) 24 36.5 ± 9.3 20 mg 48 6.1 ± 5.1 UG-191 24 58.5 ± 14.1 30 mg 48 28.3 ± 12.1 72 8.4 ± 2.4

Results of inhibition of MAO-B blood platelet activity after p.o. and transdermal administration are shown in Table 6.

Table 6. Effect of (-) - deprenyl on inhibition of MAO-B blood platelet activity (%) compared to control. The measurements were performed with a sub

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The composition, particle size and percentage of liquid crystalline state of the various control preparations were as follows:

UG-111

PEG 4000 16,0 g

PEG 400 60.0 g

Propylene glycol 8.0 g

Cremophor® EL 2.0 g

Deprenil HCL 5,0 g

PEG 400 ad 100.0 g

Average particle size: 72.7 μτη; liquid crystalline state: 20%.

UG-167 PEG 4000 19,0 g PEG 400 55,0 g Propylene glycol 8,0 g Xanthan gum 10,0 g Deprenil HCL 5.0 g PEG 400 ad 100,0 g

Average particle size: 91-109 μ, ηι; liquid crystalline state: 70-80%.

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Table 1 IC ₅₀ values of deprenyl and metabolites at MPP ⁺ uptake into striatal synaptosomes

Compound IC » M Compound IC » M (-) - deprenyl (-) - p-F-deprenyl - (-) - desmethyl-deprenyl - (-) - p-F-desmethyl-deprenyl - (+) - desmethyl-deprenyl 9,1x1ο · ⁶ (-) - p-F-methamphetamine 1,3x10 * (-) - Methamphetamine 4.9x10 ' ⁷ (-) - p-F-methamphetamine l, 3xl0 ' ⁷ (+) - Methamphetamine 9,1x1ο · ⁸ (-) - p-F-amphetamine 7,2x10 * (+) - p-F-amphetamine 1,0x10 *

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Table 2. Inhibition of uptake uptake in rat brain synaptosomes

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Table 3. Effect of post-depressant post-treatment on MPTP neurotoxicity

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Table 8

Interactions of (-) - deprenyl and (-) - p-fluoro-deprenyl metabolites with DSP-4 neurotoxicity in rats.

Previous processing mg / kg; i.p. Processing DSP-4 in% ± S.D. NA content hippocampus in% ± S.D. Survival % (-) - MA 1 50 61 ± 3.5 100 (-) - MA 5 30 116 ± 2.1 63 (-) - MA 10 50 nd * 0 (-) - p-F-MA 10 50 nd * 0

* nd: we did not specify. Due to their toxic carnivorous effects, the animals died during the first day.

MA = methylamphetamine p-F-MA = p-fluoro-methylamphetamine.

Claims (15)

PATENT APPLICATIONS A biphasic pharmaceutical preparation comprising as an active ingredient an MAO inhibitor and an uptake inhibitor together with conventional pharmaceutical excipients. The composition of claim 1, characterized in that it comprises, as an MAO inhibitor, a reversible or irreversible prolonged-action MAO inhibitor. A preparation according to claim 1, characterized in that it comprises a sustained-release uptake inhibitor. A preparation according to claim 1, characterized in that it comprises an MAO inhibitor in a mass amount of 5 to 95% and an uptake inhibitor in a mass amount of 5 to 95%. 5. The preparation of claim 1, comprising the MAO inhibitor and the uptake inhibitor in a ratio of 1 -19: 1-19. A preparation according to claim 1, characterized in that a retardation uptake inhibitor is used. A preparation according to claim 1, characterized in that it comprises N- [1-phenyl-isopropyl] -N-methyl-propynylamine hydrochloride or its optically active isomer as an MAO inhibitor. A preparation according to claim 1, characterized in that it comprises N- [4-fluoro-phenyl-isoprop-1-yl] -N-methyl-propynylamine or its optically active isomer as an MAO inhibitor. A preparation according to claim 1, characterized in that it comprises retarded N- [1-phenyl-isopropyl] -N-methyl-propynylamine hydrochloride or its optically active isomers or metabolites as an inhibitor. A preparation according to claim 1, characterized in that it comprises retarded N- [4-fluoro-phenyl-isoprop-1-yl] -N-methyl-propynylamine or its metabolite or its optically active isomers or metabolites as an inhibitor. A preparation according to claim 1, characterized in that it comprises, as an inhibitor, a compound of general formula I in which R ^{1 is a} straight or branched alkyl group, C? 10 phenylalkyl group or a phenyl group or a cycloalkyl group, R ² is a straight or branched alkyl group or an alkyl group substituted with a hydrogen atom, a hydroxy-Ci} alkoxy group, or with one or two phenyl groups, a phenyl group or a _C3 ^ cycloalkyl group , provided that R ¹ and R ² together contain at least 3 carbon atoms, or acid addition salts or metabolites thereof. A preparation according to claim 11, characterized in that it comprises as an active ingredient a compound of general formula I, wherein R ^{1 represents} an ethyl, propyl, butyl, hexyl, phenyl or phenylmethyl group. A preparation according to claim 12, characterized in that it comprises, as a compound of general formula I, N-propyl-1-phenyl-2-pentylamine or its acid addition salt, N-propyl-1-phenyl-2-butylamine or its acid addition salt or N-propyl-1-phenyl-2-hexylamine or an acid addition salt thereof. A method for the preparation of preparations according to claim 1, characterized in that the MAO inhibitor and the uptake inhibitor are mixed with conventional pharmaceutical excipients and the mixture is inherently known in the form of a pharmaceutical preparation suitable for the treatment of ongoing clinical imaging neurodegenerative processes. The method of claim 14, wherein the formulation is in the form of a two-phase pellet, tablet or transdermal preparation. For: CHINOIN GY0GYSZER- ŠS VEGYEiSZETI TERM & EK GYARA RT. F; £ 'i- · · - ·' SUMMARY Pharmaceutical preparation and process for its preparation The invention relates to a biphasic pharmaceutical composition comprising as an active ingredient an MAO inhibitor and an uptake inhibitor together with conventional pharmaceutical excipients. The preparation can be used to treat neurodegenerative diseases. Optionally, N- (1-phenyl-isopropyl) -N-methyl-propynylamine or N- (4-fluoro-phenyl) -isopropyl-1-yl-N-methyl-propynylamine or their salts, optically active isomers may be used or metabolites both as an MAO inhibitor and as an uptake inhibitor.